A major emphasis of this project has been to define the relationship of exogenous hormones to subsequent cancer risk. Using a similar approach as had been used to examine the effects of exogenous hormones on breast cancer risk, analyses within the context of a large screening program showed an association of menopausal hormone use with the risk of ovarian cancer. These analyses showed risk to increase with years of use of hormones, particularly when the preparation used was unopposed estrogens. Relationships with breast cancer are being pursued with additional follow-up data. In addition, analyses are ongoing to clarify relationships for subgroups of tumors (such as those defined by hormone receptor status). Relationships with other tumor sites (including endometrial and lung cancers) are also being pursued. Within the context of several case-control studies we have also pursued relationships with hormone replacement therapy. The latest analyses showed some evidence that hormone use might increase the risk of cervical adenocarcinomas, whereas no relationship was seen for squamous cell tumors. This variation in effect supported the notion that cervical adenocarcinomas might be more closely linked to endometrial as contrasted with cervical tumors. Also of interest is the relationship of breast implants to subsequent cancer risk. Breast cancer risk has been of concern, given that breast implants can interfere with the mammographic visualization of lesions. However, in a large retrospective study that we conducted, we found no evidence for an alteration in breast cancer risk. These patients also generally did not experience alterations in other cancer sites, although elevations were observed in the risk of lung and brain cancers, the explanation for which remains unclear. In a mortality analysis, implant patients had signficantly elevated risks of death from suicide, but other causes of death were similar to the general population. Currently underway are analyses of risk of connective tissue diseases related to breast implants. In a study conducted in collaboration with Swedish investigators, we sought to determine reasons for a reduced risk of breast cancer that has been observed following breast reduction operations. Using data abstracted from medical records, we showed that the inverse relationship was related to the amount of breast tissue removed. A retrospective cohort study is also being conducted to examine the effects on cancer risk of different causes of infertility and of different associated therapies. Of particular concern is whether the use of ovulation stimulating drugs predisposes to ovarian cancer. This study involves detailed abstraction of medical records of patients diagnosed as long ago as the 1960's and administration of questionnaires to obtained updated health information. In a separate investigation, conducted in collaboration with investigators in Denmark, cancer risk among children conceived following use of ovulation-stimulating drugs has been assessed. Preliminary analyses show no alteration in childhood cancer risk. A number of medical conditions have been suggested as predisposing to the risk of breast, endometrial and ovarian cancers, but most of these studies have relied on patients reports of these prior conditions. To obtain more precise information on the nature of these prior medical conditions, we are conducting a large case-cohort study in Denmark that involves access to details of the conditions as contained in medical records. This study will enable a thorough assessment of cancer risk in relation to details of the prior diagnoses.